The SGLT1 transporter belongs to the family of sodium-glucose cotransporters SLCA5 and is expressed in significant amounts in the membrane of the brush border of small intestine enterocytes in humans and other animals [5]. The sequence of events in this process was assumed as follows: the co-transport of Na+ and glucose by SGLT1 into the enterocyte induces depolarization of the brush border membrane, which activates the voltage-gated L-type calcium channel Cav1.3, which in turn, induces Ca2+ influx. It is believed that Cr absorption uses some . Acute effects on insulin sensitivity and diurnal metabolic profiles of a high-sucrose compared with a high-starch diet. Thompson C.S., Debnam E.S. This enzyme breaks the bonds between the monomeric sugar units of disaccharides, oligosaccharides, and starches. Cholecystokinin (CCK) is a gastrointestinal peptide secreted rapidly by I-cells in the duodenum and proximal jejunum after food intake and is also abundantly produced in the brain. An early initial peak in GLP-1 secretion triggered by the appearance of nutrients in the jejunum is associated with slowing of gastric emptying, and at lower nutrient flow rates, the duodenal absorption capacity can keep up with supply, so the overspill of nutrients into the distal gut is reduced (62). The latter may have been due to the fact that biopsy samples from the duodenum were taken after overnight fasting [21]. 4 (b) shows the associated glucose absorption in the small intestine. The activity of the sympathetic system is regulated by the hypothalamus as a part of the stress reaction but may also receive input from the gut. Recent results of a clinical trial using Hafnia alvei in overweight subjects [103], suggest that development of new probiotics influencing both glycemia and appetite may represent a promising supplementary therapy for the pharmacological treatment of metabolic diseases. Glucagon-like peptide-2 and the enteric nervous system are components of cell-cell communication pathway regulating intestinal Na(+)/glucose co-transport. Inclusion in an NLM database does not imply endorsement of, or agreement with, Rieg J.D., Chirasani V.R., Koepsell H., Senapati S., Mahata S.K., Rieg T. Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice. It does not, however, exclude an indirect effect of the rate of glucose absorption in appetite control as a part of the long-term regulation of energy metabolism, for example, by contributing to the mechanism of hyperglycemia in T2D and obesity. From the Mouth to the Stomach. This is equivalent to an induction time. After glucose ingestion, secretion of glucagon normally falls, which, together with rising glucose and insulin concentrations, accounts for the decrease in hepatic glucose production (which in the fasting state is maintained by the basal levels of glucagon reaching the liver). The World Health Organization's reduced osmolarity solution is composed of the following in mmol/L: Na + 75, Cl 65, glucose 75, K + 20 and citrate 10; . Duration of satiety of carbohydrate-rich meal is shorter than that induced by other macronutrients suggesting that postprandial changes of blood glucose, i.e., the rate of glucose absorption, may potentially influence regulation of hunger [122]. Yun S.I., Park H.O., Kang J.H. See accompanying articles, pp. Moreover, Hafnia alvei probiotic was recently shown to reduce food intake and glycemia in obese mice and overweight humans, potentially involving melanocortin-like effects of a bacterial protein caseinolytic protease B [102,103]. The results suggest that the gut microbiota play a direct role in the reduction of adiposity observed after bariatric surgery (81) and that the changes were mainly due to weight loss. The dotted lines mark preoperative basal levels. Absorption after surgery is extremely rapid, and complete absorption is obtained more rapidly than in individuals who do not undergo this surgery (Fig. See text for further analysis. Levitt M.D., Fine C., Furne J.K., Levitt D.G. Gastrointestinal function in turn is regulated by metabolic, endocrine, and neuronal signals generated in the gut or associated with vagal activity; these signals influence the secretion of gut hormones that regulate appetite (and thereby food intake), gastrointestinal motility, and pancreatic endocrine functions. digestion, absorption, and transportation. Diamond J.M., Karasov W.H., Cary C., Enders D., Yung R. Effect of dietary carbohydrate on monosaccharide uptake by mouse small intestine in vitro. These studies suggest that changes in the expression and activity of SGLT1 and GLUT2 in the small intestine are due to the appearance of nutrients in the intestine, and may also be regulated by biological clock genes [49]. However, the satiety-increasing effect of fiber-rich diets in T2D subjects is inconclusive and may depend on the individual composition of gut microbiota [124]. Restricted feeding phase shifts clock gene and sodium glucose cotransporter 1 (SGLT1) expression in rats. These signals must run in the afferent vagus or the sensory sympathetic neurons entering the medulla through the dorsal horns activating ascending tracts to the brain, but evidence suggests that the vagal mechanisms predominate (49). A second important element is the exaggerated secretion of gut peptides, including GLP-1, triggered by the rapid nutrient entry into the small intestine, leading to a spike in insulin secretion and subsequent hypoglycemia (43), as discussed next. Paracellular glucose transport plays a minor role in the unanesthetized dog. The physiological studies showed that the expression and activity of the SGLT1 and GLUT2 transporters in small intestinal enterocytes undergo both short- and long-term regulation by dietary carbohydrates as well as by regulatory factors, including peptide hormones involved in the regulation of appetite such as leptin, glucagon-like peptide-1 (GLP-1) etc. CCK is responsible for exocrine pancreatic secretion, gallbladder contraction, and intestinal motility [87]. Fernandes A.B., Alves da Silva J., Almeida J., Cui G., Gerfen C.R., Costa R.M., Oliveira-Maia A.J. If the same amount of glucose is given, the results may not be particularly remarkable, at least not with relatively small amounts of glucose (25 g or roughly one-half the amount of sugar as in a can of soda). In contrast, low-nutrient liquids empty in a monoexponential pattern without a significant lag phase, which changes to a linear pattern as nutrient density increases. In this review we discuss the mechanisms of glucose absorption in the small intestine in physiological conditions and their alterations in metabolic diseases as well as their relevance to the regulation of appetite. A fundamental feature of GLP-1 and GIP-triggered insulin secretion is their glucose dependence: unless glucose concentrations are at or above normal levels, the cAMP signal in -cells is largely ineffective. Uldry M., Ibberson M., Hosokawa M., Thorens B. GLUT2 is a high affinity glucosamine transporter. An increase in the level of the GLUT2 transporter in the basolateral membrane of enterocytes and its mRNA in the small intestine was also found in rats with streptozotocin-induced diabetes [12,13]. At the same time as they increase insulin secretion, GLP-1 and GIP modulate the release of the other pancreatic islet hormones glucagon and somatostatin. However, if the intravenous glucose infusion is adjusted so that the resulting plasma glucose concentrations are identical to those after oral or small intestinal administration of glucose, substantially more insulin is secreted with oral or enteral administration, a phenomenon known as the incretin effect (2). When the regulation of emptying is perturbed (e.g., pyloroplasty, gastric sleeve or gastric bypass operation), postprandial glycemia may reach high levels, sometimes followed by profound hypoglycemia. The role of cyclic AMP in the control of sugar transport across the brush-border and basolateral membranes of rat jejunal enterocytes. This leads to the fact that the toxins present in food can be absorbed from the intestinal lumen [44]. The authors declare no conflict of interest. This indicated that the marked increase in mRNA of the SGLT1 transporter does not depend on its carbohydrate metabolism in the body and whether it is transported with the participation of SGLT1. The physiological significance of such mechanisms may be the anticipation of carbohydrate absorption extracted from nutrients and their storage as glycogen in the liver [121]. Small intestine hexose transport in experimental diabetes. Increase of the SGLT1 protein and its mRNA in the brush border of enterocytes of the small intestine were found in patients with T2D [21,22]. Blood glucose dynamics and control of meal initiation: A pattern detection and recognition theory. After a 30-min load of glucose (25 mM) into the lumen of the rat small intestine, both in vivo and in vitro, an increase in Vmax of active glucose transport with the participation of SGLT1 in the brush border vesicles of enterocytes was observed, while both the facilitated and passive components of the absorption of this monosaccharide did not change [46]. The stimulatory effects on GLP-1 were explained by the fact that inhibition of SGLT1 in the upper part of the small intestine may decrease glucose absorption and, thereby, promotes glucose delivery to the lower parts of the intestine, where it can be metabolized by microbiota which, in turn, can stimulate GLP-1 secretion by increased production of short-chain fatty acids. prepared the figures and revised and edited the manuscript. Campfield L.A., Smith F.J. Preferential localizations of SGLT1 and GLUT2 transporters in the brush border and the basolateral membranes of enterocytes determine the rate of glucose absorption under low (<30 mM) and high (>30 mM) luminal glucose concentrations in healthy conditions. Melanson K.J., Westerterp-Plantenga M.S., Campfield L.A., Saris W.H. In addition, a coordinated change in the activities of SGLT1 and GLUT2 and their mRNA in enterocytes of the small intestine in several mammalian species under the influence of a circadian rhythm has been described [48,49]. It is now generally accepted that in the range of relatively low concentrations of glucose (less than 30 mM) in the lumen of the small intestine, for example after eating a low-carbohydrate diet, the main route of absorption of this monosaccharide through the intestinal epithelium in vivo involves its active transport across the brush border membrane of enterocytes using the Na+-glucose co-transporter (SGLT1) [4,5,6] (Figure 1). An indirect pathway involving GLP1R-dependent stimulation of somatostatin secretion seems likely because somatostatin receptors generally are coupled to inhibition of their target cells. Before nutrients are absorbed into the bloodstream, they normally are retained for some time in the stomach. By controlling appetite and energy intake, gut hormones influence the size of adipose tissue stores, which are the major determinants of peripheral insulin sensitivity. Kinetics and mechanisms of glucose absorption in the rat small intestine under physiological conditions. Glucose-sensitive nerve fibers in the intestinal mucosa and the hepatic portal system send impulses to the brain (48). Some are intrinsic to the gut and are essential parts of the absorptive process, including propulsive activity, increasing nutrient exposure to the mucosal surface, digestive and absorptive mechanisms, and intestinal blood flow. Horie I., Abiru N., Hongo R., Nakamura T., Ito A., Haraguchi A., Natsuda S., Sagara I., Ando T., Kawakami A. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. Noticeable levels of apical GLUT2 were found at glucose concentrations above 3040 mM, but much higher levels become apparent when the luminal glucose concentration exceeds 75 mM [52]. These in turn have profound effects on peripheral metabolism. The https:// ensures that you are connecting to the Changes in blood glucose levels are also involved in regulation of appetite, suggesting that glucose absorption may be relevant to hyperphagia in metabolic diseases. In studies where glucose was infused directly into the duodenum, plasma concentrations of GIP increased in approximately linear fashion with increasing rates of infusion. The relative role of different mechanisms of glucose absorption in the small intestine under physiological conditions. These enterocytes then migrate over the next 3 days to the tops of the villi, where they provide increased glucose absorption [67]. Absorption of glucose The transport of nutrients from intestinal lumen into blood stream is called absorption. 2-Deoxyglucose transport by intestinal epithelial cells isolated from the chick. An obesity-associated gut microbiome with increased capacity for energy harvest. Pennington A.M., Corpe C., Kellett G.L. GLUT2 Accumulation in enterocyte apical and intracellular membranes: A study in morbidly obese human subjects and ob/ob and high fat-fed mice. Figure 4.4. Effect of beverage temperature on intestinal absorption. Sakar Y., Nazaret C., Lettron P., Ait Omar A., Avenati M., Viollet B., Ducroc R., Bado A. It has been suggested that this stimulation is mediated by the binding of insulin to receptors in the portal vein that activate the hepatic-intestinal nerves and increase SGLT1 in the brush border of enterocytes [72]. Stomach Absorption. Gruzdkov A.A., Gromova L.V. Recently, several selective SGLT1 inhibitors (KGA-2727, GSK-1614235, LX2761, JTT-662), as well as dual SGLT2/SGLT1 inhibitors (sotagliflozin, licogliflozin) have been tested in clinical trials showing reduction of blood glucose and improvement of metabolic parameters without serious gastrointestinal side effects [8,109,113,114]. However, it has been abandoned as a potential type 2 diabetes drug due to its rapid hydrolysis to phloretin, which inhibits facilitative GLUTs transporters present in various tissues [112]. Hediger M.A., Rhoads D.B. Doctors may start this treatment if your symptoms and medical history strongly suggest this is the cause, even when test results are inconclusive or without any testing at all. Mechanisms of glucose absorption at a high carbohydrate level in the rat small intestine in vivo. Wu T., Rayner C.K., Watson L.E., Jones K., Horowitz M., Little T.J. Digested nutrients pass into the blood . In the early 2000s, it was shown that with a high carbohydrate load in the small intestine in different mammalian species, the GLUT2 transporter is localized in the brush border membrane of enterocytes, and therefore, together with the SGLT1 transporter, can participate in the absorption of glucose from the gut lumen [33]. Anini Y., Brubaker P.L. In our study, using rats with T2D caused by a high-fat diet and a low dose of streptozotocin, increased absorption of glucose in the small intestine was determined in vivo in the absence of anesthesia and surgery. These mechanisms have been studied mainly in animals, and their importance in humans is unknown. Although most gliflozins have limited potency on SGLT1, they still may affect intestinal glucose absorption [110,111]. It begins in the mouth and ends in the small intestine. Indeed, delayed satiety is a typical feature of obese humans and rodents involving long-term modifications of the brain circuitries regulating appetite, for example, the dopamine system [130]. FOIA Wright E.M., Hirsch J.R., Loo D.D., Zampighi G.A. The gastrointestinal tract plays a major role in the regulation of postprandial glucose profiles. In humans, . The suppression of glucagon secretion may contribute to the beneficial metabolic effect of GLP-1 because of the consequent reduction in hepatic glucose output (74). Among the gut hormones are the incretin hormones, which ensure that postprandial glucose excursions are kept low and relatively constant, despite variable amounts of ingested carbohydrates, through actions on insulin secretion and gut motility. drafted the manuscript. Moreover, small intestinal motility and the flow of luminal content are determinants of glucose absorption, and these are potential targets for pharmacological manipulation (37). 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Note that the small intestinal glucose absorption occurs after gastric emptying and appearance of satiation i.e., later than postprandial glucose peak, which is due to reflectory hepatic glucose production. At the same time, in recent decades, studies on various animal species have shown that an additional mechanism that promotes the absorption of glucose in the small intestine in the range of its high concentrations in the intestinal lumen may also be facilitated diffusion across the brush border membrane of enterocytes with the participation of GLUT2 transporters, which are able to quickly integrate into this membrane [4,6]. One of the ways to illustrate the role of the gut in glucose homeostasis is to compare the fate of glucose that has been administered orally or infused intravenously. Moreover, a quantitative evaluation of the relative contribution of different mechanisms of glucose absorption to the total glucose absorption may also depend on the method of calculation of the corresponding kinetic constants; in particular, whether the effects of the pre-epithelial diffusion layer and the peculiarities of the intestinal absorptive surface (presence of villi) are included in the calculations [28,59,60].
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